U.S. patent application number 15/122387 was filed with the patent office on 2017-03-09 for phosphodiesterase-4 inhibiting phytochemical compositions.
This patent application is currently assigned to Nature's Sunshine Products, Inc.. The applicant listed for this patent is Nature's Sunshine Products, Inc.. Invention is credited to John G. Babish, Clinton J. Dahlberg, Matthew L. Tripp.
Application Number | 20170065652 15/122387 |
Document ID | / |
Family ID | 54009636 |
Filed Date | 2017-03-09 |
United States Patent
Application |
20170065652 |
Kind Code |
A1 |
Tripp; Matthew L. ; et
al. |
March 9, 2017 |
Phosphodiesterase-4 Inhibiting Phytochemical Compositions
Abstract
Phosphodiesterase-4 (PDE4) inhibiting compositions comprising a
Sceletium and an activity enhancer are disclosed and described.
Methods and systems for inhibiting PDE4, as well as, dosage forms
comprising a Sceletium extract and an activity enhancer are also
disclosed. Additionally disclosed are methods for enhancing the
potency or PDE4 inhibitory activity of a Sceletium extract by
addition of an activity enhancer.
Inventors: |
Tripp; Matthew L.; (Saratoga
Springs, UT) ; Dahlberg; Clinton J.; (Saratoga
Springs, UT) ; Babish; John G.; (Brooktondale,
NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Nature's Sunshine Products, Inc. |
Lehi |
UT |
US |
|
|
Assignee: |
Nature's Sunshine Products,
Inc.
Lehi
UT
|
Family ID: |
54009636 |
Appl. No.: |
15/122387 |
Filed: |
February 26, 2015 |
PCT Filed: |
February 26, 2015 |
PCT NO: |
PCT/US2015/017857 |
371 Date: |
August 29, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61966704 |
Feb 28, 2014 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 33/06 20130101;
A61P 3/10 20180101; A61K 31/51 20130101; A61K 31/51 20130101; A61P
35/00 20180101; A61K 31/717 20130101; A61K 31/555 20130101; A61K
31/198 20130101; A61K 31/555 20130101; A61K 31/717 20130101; A61P
3/00 20180101; A61K 2300/00 20130101; A61K 36/185 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 33/06 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 36/185 20130101; A61K 31/198 20130101; A61K 9/0053 20130101;
A61P 25/00 20180101 |
International
Class: |
A61K 36/185 20060101
A61K036/185; A61K 31/51 20060101 A61K031/51; A61K 9/00 20060101
A61K009/00; A61K 31/198 20060101 A61K031/198 |
Claims
1. A phosphodiesterase type IV (PDE4) activity inhibiting
formulation, comprising: an Sceletium extract in combination with
at least one activity enhancer, wherein when administered to a
subject, the formulation is more effective at inhibiting PDE4
activity than either the Sceletium extract or the activity enhancer
alone.
2. The formulation of claim 1, wherein the PDE4 inhibiting effect
of the formulation on the subject is more than an additive effect
achieved by administering the Sceletium extract or the activity
enhancer alone.
3. The formulation of claim 1, wherein the PDE4 inhibiting effect
of the formulation on the subject is from about 30% to about 80%
greater than that achieved by administering either the Sceletium
extract or the activity enhancer alone.
4. The formulation of claim 1, wherein the Sceletium extract is
from at least one of S. tortuosum, S. strictum, S. subvelutinum, S.
joubertii, and S. namaquense or a combination thereof.
5. The formulation of claim 4, wherein the Sceletium extract is
from S. tortuosum.
6. The formulation of claim 1, wherein the Sceletium extract
comprises from about 1 wt % to about 50 wt % of the
formulation.
7. The formulation of claim 1, wherein the activity enhancer has
substantially no PDE4 inhibitory effect of its own.
8. The formulation of claim 1, wherein the activity enhancer is a
member selected from the group consisting of: L-theanine, thiamine,
zinc gluconate, magnesium citrate, magnesium stearate, cellulose,
or a mixture thereof.
9. The formulation of claim 8, wherein the at least one activity
enhancer is L-theanine.
10. The formulation of claim 8, wherein the at least one activity
enhancer is thiamine.
11. The formulation of claim 1, wherein the at least one activity
enhancer comprises from about 1 wt % to about 75 wt % of the
formulation.
12. The formulation of claim 1, wherein the formulation further
comprises a pharmaceutically acceptable carrier.
13. The formulation of claim 1, wherein the formulation is an oral
dosage formulation.
14. The formulation of claim 13, wherein the oral dosage form
comprises a capsule, a tablet, a powder, a beverage, a syrup, a
suspension, or a food.
15. The formulation of claim 14, wherein the formulation comprises
from about 0.1 mg to about 10,000 mg of the Sceletium extract.
16. A Sceletium extract dosage form for administration to a subject
to inhibit phosphodiesterase type IV (PDE4) activity comprising: an
amount of a Sceletium extract and an amount of at least one
activity enhancer, wherein when administered to a subject, the
dosage is more effective at inhibiting PDE4 than either the amount
of Sceletium extract or the amount of the activity enhancer
alone.
17. The dosage form of claim 16, wherein the amount of Sceletium
extract is a therapeutically effective amount without the activity
enhancer.
18. The dosage form of claim 16, wherein the amount of the
Sceletium extract is from about 0.01 mg to about 30,000 mg.
19. The dosage form of claim 16, wherein the amount of the
Sceletium extract is from about 0.01 mg to about 10,000 mg.
20. The dosage form of claim 16, wherein the wherein the amount of
the Sceletium extract is from about 0.1 mg to about 100 mg.
21. The dosage form of claim 16, wherein the amount of the at least
one activity enhancer is from about 0.01 mg to about 10,000 mg.
22. The dosage form of claim 16, wherein the amount of the at least
one activity enhancer is from about 1 mg to about 125 mg.
23. The dosage form of claim 16, wherein the Sceletium extract is
present at an amount of from about 1 mg to about 100 mg and the at
least one activity enhancer is present in an amount of from about 1
mg to about 125 mg.
24. The dosage form of claim 16, wherein the dosage is prepared for
administration to a subject according to a predetermined
regimen.
25. The dosage form of claim 24, wherein the regimen is a once per
day administration.
26. The dosage form of claim 16, wherein the dosage is one of an
oral dosage form, a transdermal dosage form, a transmucosal dosage
form, an inhalant dosage form, or a parenteral dosage form.
27. A method of inhibiting phosphodiesterase type IV (PDE4)
activity in a subject comprising: administering an amount of a
Sceletium extract and at least one activity enhancer to the
subject.
28. The method of claim 27, wherein the PDE4 inhibition provides
treatment of signs or symptoms of a condition selected from the
group consisting of: anxiety related disorders, depression related
disorders, allergic disorders, autoimmune disorders, diabetes
associated disorders, inflammatory conditions, neurological
disorders, or cardiovascular diseases.
29. The method of claim 27, wherein the condition is an anxiety
related disorder.
30. The method of claim 27, wherein the condition is a depression
related disorder.
31. The method of claim 27, wherein the treatment is
prophylactic.
32. The method of claim 27, wherein the Sceletium extract and at
least one activity enhancer are administered concurrently.
33. The method of claim 27, wherein the Sceletium extract and at
least one activity enhancer are administered separately.
34. The method of claim 27, wherein the Sceletium extract and the
at least one activity enhancer are coadministered from a single
formulation.
35. A method of increasing phosphodiesterase type IV (PDE4)
inhibition activity of an amount of a Sceletium extract comprising:
adding an amount of at least one activity enhancer, wherein the
combination of Sceletium extract and the at least one activity
enhancer inhibits PDE4 activity to a greater degree than the amount
of Sceletium alone.
36. The method of claim 35, wherein the at least one activity
enhancer is added to a formulation containing the Sceletium
extract.
37. The method of claim 35, wherein the at least one activity
enhancer is added to the Sceletium extract upon administration of
the activity enhancer to a subject.
38. The method of claim 35, wherein the increase in PDE4 inhibition
activity is more than an additive effect of administering the
amount of Sceletium extract and the amount of at least one activity
enhancer alone.
39. The method of claim 35, wherein the amount of at least one
activity enhancer is added to the amount of Sceletium extract at a
ratio of from about 1:1 to about 20:1.
Description
PRIORITY DATA
[0001] This application claims priority benefit to United States
Provisional Patent Application Ser. No. 61/966,704 filed on Feb.
28, 2014 which is incorporated herein by reference. This
application also incorporates by reference Patent Cooperation
Treaty application serial no. PCT/US2015/017858 filed on Feb. 26,
2015 under Thorpe North & Western attorney docket no.
3901-003.PCT.
BACKGROUND
[0002] Phosphodiesterase type 4 (PDE4) is an enzyme that degrades
the phosphodiester bond in the second messenger molecules of
cellular cyclic adenosine monophosphate (cAMP), thereby regulating
the localization, duration, and amplitude of cAMP signaling. cAMP
binds to protein kinases enabling catalytic units of the protein
kinases to phosphorylate substrate proteins. cAMP functions in
several biochemical processes. The specific effect of cAMP depends
on the protein kinase acted upon and the cell type. Sustaining
cellular cAMP levels can inhibit numerous diseases and conditions.
PDE4 inhibitors block the PDE4 induced degradation of cAMP thereby
sustaining cellular cAMP levels and prolonging the effects of cAMP
mediated physiological processes. Accordingly, PDE4 inhibitors can
be valuable agents in treating or managing a number of related
diseases or conditions.
[0003] Unfortunately, several PDE4 inhibiting compounds have narrow
therapeutic windows and often cause undesirable side effects (i.e.
nausea, diarrhea and headaches) when administered at
therapeutically effective doses. Additionally, consumers continue
to demand pharmaceuticals and nutraceuticals that include naturally
derived active ingredients. Accordingly, the present inventors
recognize a need for naturally derived PDE4 inhibitors which attain
a desired level of PDE4 inhibition with little to no adverse side
effects.
BRIEF DESCRIPTION OF THE FIGURES
[0004] Features and advantages of the invention will be apparent
from the detailed description that follows, and which taken in
conjunction with the accompanying FIGURE, together illustrate
features of the invention. It is understood that this drawing
merely depicts exemplary effects of PDE inhibition and is not,
therefore, to be considered limiting of its scope.
[0005] FIG. 1 shows a schematic diagram of various tissue responses
resulting from inhibition of PDE4.
DETAILED DESCRIPTION
[0006] Reference will now be made to exemplary invention
embodiments and specific language will be used herein to describe
the same. It will nevertheless be understood that no limitation in
scope is thereby intended. Alterations and further modifications of
inventive features described herein, and additional applications of
inventive principles which would occur to one skilled in the
relevant art having possession of this disclosure, are to be
considered as inventive subject matter. Further, before particular
embodiments are disclosed and described, it is to be understood
that this disclosure is not limited to the particular process and
materials disclosed herein as such may vary to some degree. It is
also to be understood that the terminology used herein is used for
the purpose of describing particular embodiments only and is not
intended to be limiting.
[0007] It must be noted that, as used in this specification and the
appended claims, the singular forms "a," "an," and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "an activity enhancer" includes one
or more of such enhancers.
[0008] As used herein, the term "about" refers to a degree of
deviation based on experimental error typical for the particular
property identified. The latitude provided the term "about" will
depend on the specific context and particular property and can be
readily discerned by those skilled in the art. When used in
connection with a numerical value, the term "about" is used to
provide flexibility and allow the given value to be "a little
above" or "a little below" the specific number stated. Further,
unless otherwise stated, the term "about" shall expressly include
"exactly," consistent with the discussion below regarding ranges
and numerical data.
[0009] As used herein, a "subject" refers to an organism that
produces PDE4 in the course of its cellular function. In one
aspect, a subject can be a mammal. In another aspect, a subject can
be a human. In another aspect, the subject can be of either male or
female gender.
[0010] As used herein, "activity enhancer" refers to any agent or
combination of agents that increases PDE4 inhibition when combined
with Sceletium, or a sceletium extract as compared to the Sceletium
or sceletium extract alone. In some embodiments, the amount of
increase can exceed the additive effect that would be achieved by
the Sceletium or sceletium extract and the activity enhancer
individually. This synergistic (i.e. more than additive) effect can
occur when both the Sceletium or sceletium extract and the activity
enhancer have PDE4 inhibitory activity, or when only the Sceletium
or sceletium extract has PDE4 inhibitory activity. For example if
F1 produces response X, F2 produces response Y, then the
combination of F1+F2>X+Y. In some situations F2 produces no
response and the value for Y is equal to zero.
[0011] As used herein, "compounds" may be identified either by
their chemical structure, chemical name, or common name. When the
chemical structure, chemical name, or common name conflict, the
chemical structure is determinative of the identity of the
compound. The compounds described herein may contain one or more
chiral centers and/or double bonds and therefore, may exist as
stereoisomers, such as double-bond isomers (i.e., geometric
isomers), enantiomers or diastereomers. Accordingly, the chemical
structures depicted herein encompass all possible enantiomers and
stereoisomers of the illustrated or identified compounds including
the stereoisomerically pure form (e.g., geometrically pure,
enantiomerically pure or diastereomerically pure) and enantiomeric
and stereoisomeric mixtures. Enantiomeric and stereoisomeric
mixtures can be resolved into their component enantiomers or
stereoisomers using separation techniques or chiral synthesis
techniques well known to the skilled artisan. The compounds may
also exist in several tautomeric forms including the enol form, the
keto form and mixtures thereof. Accordingly, the chemical
structures encompass all possible tautomeric forms of the
illustrated or identified compounds. The compounds described also
encompass isotopically labeled compounds where one or more atoms
have an atomic mass different from the atomic mass conventionally
found in nature. Examples of isotopes that may be incorporated into
the compounds of the invention include, but are not limited to,
.sup.2H, .sup.3H, .sup.13C, .sup.4C, .sup.15N, .sup.18O, .sup.17O,
etc. Compounds may exist in unsolvated forms as well as solvated
forms, including hydrated forms and as N-oxides. In general,
compounds may be hydrated, solvated or N-oxides. Certain compounds
may exist in multiple crystalline or amorphous forms. Also
contemplated are congeners, analogs, hydrolysis products,
metabolites and precursor or prodrugs of the compound. In general,
all physical forms are equivalent for the uses contemplated herein
and are intended to be within the scope of the present
disclosure.
[0012] In this disclosure, "comprises," "comprising," "comprised,"
"containing" and "having" and the like can have the meaning
ascribed to them in U.S. Patent law and can mean "includes,"
"including," and the like, and are generally interpreted to be open
ended terms. The term "consisting of" is a closed term, and
includes only the methods, compositions, components, systems,
steps, or the like specifically listed, and that which is in
accordance with U.S. Patent law. "Consisting essentially of" or
"consists essentially" or the like, when applied to devices,
methods, compositions, components, structures, steps, or the like
encompassed by the present disclosure, refer to elements like those
disclosed herein, but which may contain additional structural
groups, composition components, method steps, etc. Such additional
devices, methods, compositions, components, structures, steps, or
the like, etc., however, do not materially affect the basic and
novel characteristic(s) of the devices, compositions, methods,
etc., compared to those of the corresponding devices, compositions,
methods, etc., disclosed herein. In further detail, "consisting
essentially of" or "consists essentially" or the like, when applied
to the methods, compositions, components, systems, steps, or the
like encompassed by the present disclosure have the meaning
ascribed in U.S. Patent law and is open-ended, allowing for the
presence of more than that which is recited so long as basic or
novel characteristics of that which is recited is not changed by
the presence of more than that which is recited, but excludes prior
art embodiments. In this specification when using an open ended
term, like "comprising" or "including," it is understood that
direct support should be afforded also to "consisting essentially
of" language as well as "consisting of" language as if stated
explicitly and vice versa. Each term provides support for the
others as if expressly stated.
[0013] As used herein. "formulation" and "composition" can be used
interchangeably and refer to a combination of at least two
ingredients. In some embodiments, at least one ingredient may be an
active agent or otherwise have properties that exert physiologic
activity when administered to a subject.
[0014] As used herein, "active agent" refers to a molecule,
compound, mixture, or ingredient that has a measurable physiologic
effect on a subject when administered thereto in an appreciable
amount, such as an effective, or therapeutically effective amount.
Like terms such as "active fraction," "active component," and
"active constituent" can be used interchangeable therewith.
[0015] Concentrations, amounts, and other numerical data may be
expressed or presented herein in a range format. It is to be
understood that such a range format is used merely for convenience
and brevity and thus should be interpreted flexibly to include not
only the numerical values explicitly recited as the limits of the
range, but also to include all the individual numerical values or
sub-ranges encompassed within that range as if each numerical value
and sub-range is explicitly recited. As an illustration, a
numerical range of "about 0.01 mg to 2.0 mg" should be interpreted
to include not only the explicitly recited values of about 0.01 mg
to about 2.0 mg, but also include individual values and sub-ranges
within the indicated range. Thus, included in this numerical range
are individual values such as 0.5 mg, 0.7 mg, and 1.5 mg, and
sub-ranges such as from 0.5 mg to 1.7 mg, from 0.7 mg to 1.5 mg,
and from 1.0 mg to 1.5 mg, etc. This same principle applies to
ranges reciting only one numerical value. Furthermore, such an
interpretation should apply regardless of the breadth of the range
or the characteristics being described.
[0016] As used herein, a "derivative" is a compound obtained from a
source compound an analog, homolog tautomeric form, stereoisomer,
polymorph, hydrate, pharmaceutically acceptable salt or
pharmaceutically acceptable solvate thereof, by a simple chemical
process converting one or more functional groups, by means of
oxidation, hydrogenation, alkylation, esterification, halogenation
and the like. The term "analog" refers to a compound having a
structure similar to that of another one, but differing from it
with respect to a certain component. The compound may differ in one
or more atoms, functional groups, or substructures, which may be
replaced with other atoms, groups, or substructures. In one aspect,
such structures possess at least the same or a similar therapeutic
efficacy for a given indication. The term "tautomer" or "tautomeric
form" refers to structural isomers of different energies which are
interconvertible via a low energy barrier. The term "stereoisomer"
refers to one of a set of isomers whose molecules have the same
number and kind of atoms bonded to each other, but which differ in
the way these atoms are arranged in space. The term "polymorph"
refers to crystallographically distinct forms of a substance. In
addition, an agent can be said to be "derived" from a source
containing many compounds or agents, such as a plant, fungus,
bacteria, or other organism. In this context, the agent can be
described or otherwise referred to in terms of its source, rather
than by its own properties, characteristics, name, or attributes
per se. For example, an extract obtained from a plant may be
described as "derived" from the plant.
[0017] The phrase "effective amount," "therapeutically effective
amount," or "therapeutically effective rate(s)" of an active
ingredient refers to a non-toxic, but sufficient amount or delivery
rates of the active ingredient, to achieve therapeutic results in
treating a disease or condition for which the drug is being
delivered. It is understood that various biological factors may
affect the ability of a substance to perform its intended task.
Therefore, an "effective amount," "therapeutically effective
amount," or "therapeutically effective rate(s)" may be dependent in
some instances on such biological factors. Further, while the
achievement of therapeutic effects may be measured by a physician
or other qualified medical personnel using evaluations known in the
art, it is recognized that individual variation and response to
treatments may make the achievement of therapeutic effects a
subjective decision. The determination of a therapeutically
effective amount or delivery rate is well within the ordinary skill
in the art of pharmaceutical sciences and medicine.
[0018] The term "extract" includes any parts of, or a material
derived from, the raw material of a particular source. Extracts may
take many forms including but not limited to: solid, liquid,
particulate, chopped, distillate, etc. and may be performed by any
number of procedures or protocols, such as chopping, grinding,
pulverizing, boiling, steaming, soaking, steeping, applying a gas,
etc., and may employ any suitable reagents, such as water, alcohol,
steam, or other organic materials. A wide number of extraction
methods and techniques are known to those of ordinary skill in the
art. In some embodiments, extracts can be made from specific parts
of a source, such as the aerial parts of a plant, the roots of a
plant, the mycelium of a fungus, etc. In some aspects and extract
may include one or more active fractions or active agents.
[0019] As used herein, a"liquid extract" refers to those substances
prepared using a solvent, e.g., ethanol, water, steam, superheated
water, methanol, hexane, chloroform liquid, liquid CO.sub.2, liquid
N.sub.2, propane, supercritical CO.sub.2 or any combination
thereof. Liquid extracts, as used herein, can refer to a dried
powder or other solid form derived from a source using a liquid
extract as a step in the overall extraction protocol. Liquid
extracts typically have a given purity percentage and can be
relatively to highly pure. In some aspects, the purity of an
extract can be controlled by, or be a function of the extraction
process or protocol.
[0020] As used herein "PDE4-associated pathologies," "PDE4 related
conditions," "PDE4 related diseases," and the like are used
interchangeably and refer to diseases or conditions related to or
caused by the degradation of cellular cAMP by PED4. A number of
exemplary PDE4 related conditions are enumerated herein.
[0021] As used herein, "oxidative stress" refers to an imbalance
between the manifestation of reactive oxygen species (ROS) and a
biological system's ability to readily detoxify the reactive
intermediates. ROS result in the formation of free radicals. Free
radicals (e.g. hydroxyl, nitric acid, superoxide) or the
non-radicals (e.g. hydrogen peroxide, lipid peroxide) damage
(called oxidative damage) specific molecules with consequential
injury to cells or tissue. Disturbances in the normal redox state
of cells can cause toxic effects through the production of
peroxides and free radicals that damage all components of the cell,
including proteins, lipids, and DNA. While short term oxidative
stress can be beneficial; over time oxidative stress can be
involved in the etiology of many diseases, such as atherosclerosis,
type 1, type 2, and type 3 diabetes, Parkinson's disease, cardiac
arrest, myocardial infarction, Alzheimer's disease, Fragile X
syndrome, and chronic fatigue syndrome. Increasing intracellular
concentrations of cAMP through the inhibition of PDE4 can have a
salutary effect on cells stressed by ROS.
[0022] As used herein, "Sceletium" refers to a plant in the plant
genus Sceletium, which is a member of the subfamily
Mesembrvanthemacease of the family Azioacae. Sceletium are low
growing succulent herbs commonly found in South Africa. Sceletium
spp. (i.e. species) include but are not limited to: S. tortuosum,
S. strictum, S. subvelutinum. S. joubertii, and S. namaquense.
[0023] As used herein, "Sceletium extract" refers to extracts that
are derived from the raw material of any part of a plant in the
plant genus Sceletium. Extracts can be made from and/or contain the
material of specific species such as S. tortuosum, S. strictum, S.
subvelutinum, S. joubertii, and S. namaquense or a combination
thereof. Additionally, in some embodiments, extracts can be made or
derived from specific parts of a Sceletium plant, such as the
aerial parts (i.e. above ground parts, such as leaves, flowers,
fruit, stems, seeds, etc.) or the roots.
[0024] As used herein, "substantial" or "substantially" when used
in reference to a quantity or amount of a material, or a specific
characteristic thereof, refers to an amount that is sufficient to
provide an effect that the material or characteristic was intended
to provide. The exact degree of deviation allowable may in some
cases depend on the specific context. Similarly, "substantially
free of" or the like refers to the lack of an identified element or
agent in a composition. Particularly, elements that are identified
as being "substantially free of" are either completely absent from
the composition, or are included only in amounts which are small
enough so as to have no measurable effect on the composition.
[0025] The terms "treat." "treating," or "treatment" as used herein
and as well understood in the art, mean an approach for obtaining
beneficial or desired results, including without limitation
clinical results in a subject being treated. Beneficial or desired
results can include, but are not limited to, alleviation or
amelioration of one or more signs or symptoms of a condition,
diminishment of extent of disease, stabilizing (i.e. not worsening)
the state of a disease or condition, delaying or slowing of disease
progression, amelioration or palliation of the disease state,
diminishment of the reoccurrence of disease, and remission (whether
partial or total), whether detectable or undetectable. "Treat,"
"treating" and "treatment" can also mean prolonging survival as
compared to expected survival if not receiving treatment and can be
prophylactic. Such prophylactic treatment can also be referred to
as prevention or prophylaxis of a disease or condition. The
prophylaxis may be partial or complete. Partial prophylaxis may
result in the delayed onset of a physiological condition.
[0026] As used herein, "pharmaceutically acceptable" refers
generally to materials which are suitable for administration to a
subject in connection with an active agent or ingredient. For
example, a "pharmaceutically acceptable carrier" can be any
substance or material that can be suitably combined with an active
agent to provide a composition or formulation suitable for
administration to a subject. Excipients, diluents, and other
ingredients used in or used to prepare a formulation or composition
for administration to a subject can be used with such term.
[0027] Comparative terms such as "more effectively," "greater
than," "improved," "enhanced," and like terms can be used to state
a result achieved or property present in a formulation or process
that has a measurably better or more positive outcome than the
thing to which comparison is made. In some instances comparison may
be made to the prior art.
[0028] As used herein, a plurality of items, structural elements,
compositional elements, and/or materials may be presented in a
common list for convenience. However, these lists should be
construed as though each member of the list is individually
identified as a separate and unique member. Thus, no individual
member of such list should be construed as a de facto equivalent of
any other member of the same list solely based on their
presentation in a common group without indications to the
contrary.
[0029] Any steps recited in any method or process claims may be
executed in any order and are not limited to the order presented in
the claims unless otherwise stated.
[0030] The present disclosure relates to extracts derived from the
plant genus Sceletium. Plants of the genus Sceletium can be
considered among the most commercially promising plants indigenous
to South Africa, with potential for use in dietary supplements,
natural medicines, and veterinary and pharmacologic products.
Sceletium spp. are found throughout the southwestern portion of
South Africa in arid environments and are distinguishable on the
basis of different vegetative, flower, fruit, and seed
characteristics.
[0031] Historically, Sceletium was used by local individuals in
aboriginal medicinal and tribal practices. In one example, S.
tortuosum was chewed, smoked, or used as a snuff that produced
euphoria and alertness that gently fade into relaxation.
Additionally, the Hottentots of Southern Africa used S. tortuosum
as a mood enhancer, relaxant, and empathogen. When chewed in
sufficient quantities Sceletium has mild anesthetic properties in
the mouth, much like kava. Sceletium was used by the San tribes for
tooth extraction, or in smaller doses, for children with colic.
Furthermore, a tea made from Sceletium was sometimes used to wean
alcoholics off alcohol. Moreover, Sceletium was used as a
psychotropic in tincture form and more recently for applications in
promoting a sense of well-being, relieving stress in healthy
individuals and for treating clinical anxiety and depression.
[0032] Alkaloids are one type of active agent in Sceletium. The
known alkaloids can be categorized into four groups: (1)
3a-aryl-cis-octahydroindoles (e.g., mesembrine), (2)
C-secomesembrine alkaloids (e.g., joubertiamine), (3) alkaloids
containing a 2,3-disubstituted pyridine moiety and two nitrogen
atoms (e.g., Sceletium alkaloid A4), and (4) a ring C-seco
Sceletium alkaloid A4 group (e.g., tortuosamine). The
3a-aryl-cos-octahydroindole group of alkaloids, includes
mesembrine, mesembranol, and mesembranone. The pharmacologic
activities of this 3a-aryl-cos-octahydroindole group of alkaloids,
include anxiolytic or antianxiety effects as well as
anti-depressive effects. The mesembrine-like alkaloids are have
central nervous system effects which include an ability to inhibit
serotonin-re-uptake (SSRI) and PDE4 activity. A standardized
extract of the plant could include dual PDE4 inhibition and 5-HT
reuptake inhibition, a combination that might offer potential
therapeutic advantages.
[0033] While it is known that the alkaloids of S. tortuosum have
anti-depressant or anti-anxiety effects due to the inhibition of
serotonin re-uptake and PDE4 inhibition, the present inventors know
of no evidence of formulations or combinations of ingredients that
would enhance these activities, or otherwise enhance PDE4
inhibition relative to other PDE isozymes. Additionally, many PDE4
inhibiting compounds have narrow therapeutic windows and often
cause undesirable side effects (nausea, diarrhea and headaches) at
doses sufficient to have a therapeutic effect. Therefore, the
present inventors have identified a need for compositions or
formulations including PDE4 inhibitors that can be administered at
therapeutically effective doses and do not exhibit undesirable side
effects when administered at such levels.
[0034] A phosphodiesterase (PDE) is any enzyme that breaks a
phosphodiester bond. The most commonly known PDEs are the cyclic
nucleotide PDEs that degrade the phosphodiester bond in the second
messenger molecules cAMP and cyclic guanosine monophosphate (cGMP).
In doing so, PDEs regulate the localization, duration, and
amplitude of cyclic nucleotide downstream signaling within
subcellular domains. PDEs are therefore important regulators of
signal transduction mediated by these second messenger molecules.
The 21 genes of the superfamily of PDE enzymes have been classified
into 11 families designated PDE1-PDE11 in mammals. This
classification is based upon amino acid sequences, substrate
specificities, regulatory properties, pharmacological properties,
and tissue distribution. With respect to substrate specificity,
PDE4, 7, and 8 are cAMP-selective hydrolases; PDE5, 6 and 9 are
cGMP-selective; and PDE1, 2, 3, 10, and 11 can hydrolyze both cAMP
and cGMP. The dual specificity of these later PDEs allows for
cross-regulation of the cAMP and cGMP pathways.
[0035] FIG. 1 shows exemplary effects of PDE inhibition on cyclic
nucleotide degradation in various tissues and physiological
processes mediated by cAMP or cGMP. This modulation of the
downstream signaling pathways relating to cAMP and cGMP can result
in profound alterations in cellular signal transduction pathways
and reflects metabolic changes associated with the specific PDE
inhibitor.
[0036] Phosphodiesterase type IV (PDE4) inhibitors increase or
prolong concentrations of intracellular cAMP resulting in the
inhibition of PDE4 activity. Several diseases and conditions are
related to processes mediated via protein phosphorylation through
PDE4. These diseases and conditions include but are not limited to
include: autoimmune disorders, allergic or inflammatory disorders,
metabolic syndrome or diabetes associated disorders, cancer, ocular
disorders, neurological disorders, mild to moderate depression,
anxiety related disorders, psychological and psychiatric disorders
where anxiety is present, major depressive episodes, alcohol and
drug dependence, bulimia nervosa, obsessive-compulsive disorders
and cognitive defects in AD.
[0037] In one exemplary invention embodiment, there is provided a
PDE4 activity inhibiting formulation. The formulation comprises a
Sceletium extract in combination with at least one activity
enhancer. The combination of the activity enhancer with Sceletium
extract can improve the PDE4 inhibiting activity to beyond the
level of inhibition that is achieved by administering the Sceletium
extract or the activity enhancer alone. In some embodiments, the
combination is more effective than the additive effect achieved by
administering the Sceletium extract or the activity enhancer alone.
In some embodiments, the effect can be about 20% greater, 25%
greater, 30% greater, 35% greater, 40% greater, 45% greater,
50%/greater, 55%/greater, 60% greater 65% greater, 70% greater, 75%
greater, 80% greater, 85% greater, or even 90% greater than the
inhibitory effect achieved by administering either the Sceletium
extract or the activity enhancer alone. In other embodiments, the
effect can be from about 30% to about 80% greater, from about 25%
to about 75% greater, from about 35% to about 85% greater, from
about 20% to about 60% greater, from about 25% to about 50%
greater, or from about 30% to about 45% greater than the inhibitory
effect achieved by administering either the Sceletium extract or
the activity enhancer alone. In some embodiments, the enhanced PDE4
inhibitory effect can be synergistic.
[0038] The Sceletium extract can be derived from any parts of or a
material derived from the raw materials of a Sceletium species. In
one exemplary embodiment, the Sceletium extract is from at least
one of: S. tortuosum, S. strictum, S. subvelutinum, S. joubertii,
S. namaquense or a combination thereof. In another embodiment, the
Sceletium extract can be derived from S. tortuosum. In some
embodiments, the extract can be derived from aerial portions of the
Sceletium plant. In other embodiments the extract can be derived
from the plants roots, stems, leaves, flowers, or a combination
thereof. The extract can be a liquid extract, a powder, a compound,
or a mixture thereof. The Sceletium extract can be present in the
formulation in an amount of from about 1 wt % to about 50 wt %,
from about 1 wt % to about 25 wt %, from about 2.5 wt % to about 20
wt %, or from about 3 wt % to about 15 wt %.
[0039] In some embodiments, at least one activity enhancer is
combined with the Sceletium extract in the formulation. The
activity enhancer can be any compound that increases PDE4
inhibition when combined with Sceletium extract. The activity
enhancer can be in the form of an extract, compound, mineral,
pharmaceutically acceptable salt, or any other form that is
suitable of being placed in a desired formulation. In some
embodiments, the activity enhancer is incapable or substantially
incapable of inhibiting PDE4 activity on its own.
[0040] A wide range of compounds and agents can be used as activity
enhancers for the Sceletium extract. In one embodiment, the
activity enhancer can be an amino acid or an amino acid analog.
Exemplary amino acids include without limitation, L-theanine,
theanine, L-glutamic acid, L-L glutamate, L-glutamine, alanine,
arginine, asparagine, ethylamine, glutamate, glutamine, histidine,
isoleucine, leucine, lysine, methionine, phenylalanine, serine,
threonine, tryptophan, tyrosine, and valine. In another embodiment,
the activity enhancer can be a metal or a compound having a metal.
Exemplary metals and metal compounds include without limitation,
magnesium, calcium, strontium, zinc, magnesium carbonate, magnesium
chloride, magnesium citrate, magnesium, hydroxide, magnesium oxide,
magnesium sterate, magnesium sulfate, calcium citrate, calcium
gluconate, calcium phosphate, calcium stearate, zinc acetate, zinc
gluconate, zinc oxide, and zinc sulfate. In yet another embodiment,
the activity enhancer can be a vitamin, an analog of a vitamin, a
salt of a vitamin, or a phosphorylated derivative of a vitamin.
Exemplary vitamins include without limitation, acefurtiamine,
acetiamine, allithiamine, beclotiamine, benfotiamine, bentiamine,
bisbentiamine, cetotoiamine, cycotiamine, fursultiamine,
monophosphothiamine, octotiamine, prosultiamine, sulbutiamine,
vintiamol, adenosine thiamine diphosphate, adenosine thiamine
triphosphate, thiamine diphosphate, thaimine mononitrate, thiamine
monophosphate, thiamine triphosphate, adenine, adenylic acid,
biotin, catechol, cobalamins, folic acid, niacin, nicotinic acid,
pantothenic acid, pyridoxine, pyridoxal, pyridoxamine riboflavin,
thiamine, retinol, ascorbic acid, calciferol, tocopherol, and
phylloquinone. In a further embodiment, the activity enhancer can
be a polysaccharide. Exemplary polysacharides include without
limitation, arabinoxylans, cellodextrins, cellulose, glycogen,
hemicellulose, pectins, and starch. In one exemplary embodiment,
the activity enhancer can be any member selected from the group
consisting of: L-theanine, thiamine, zinc gluconate, magnesium
citrate, magnesium stearate, cellulose, or mixtures thereof. In
another embodiment, the activity enhancer is L-theanine. In yet
another embodiment, the activity enhancer is thiamine. In a further
embodiment, the formulation comprises a plurality of activity
enhancers. The plurality of activity enhancers can include any
combination of the activity enhancer types (i.e. amino acids,
metals, vitamins, and polysaccharides) discussed above. In one
embodiment, the activity enhancers can include L-theanine and
thiamine. In another embodiment, the activity enhancers can include
L-theanine, thiamine, magnesium citrate, and zinc. In an additional
embodiment, the activity enhancer can include L-theanine, thiamine,
magnesium citrate, zinc, and magnesium stearate. The amount of
activity enhancer can be selected in view of the specific compound
used and the desired properties of the final formulation. However,
in one embodiment, the activity enhancer can be present in the
formulation in an amount of from about 1 wt % to about 90 wt %,
from about 5 wt % to about 85 wt %, from about 10 wt % to about 80
wt %, from about 1 wt % to about 75 wt %, or from about 1 wt % to
about 50 wt %.
[0041] In one exemplary embodiment, the Sceletium extract is
present in the formulation in an amount of from about 1 wt % to
about 50 wt % and the at least one activity enhancer is present
from about 1 wt % to about 90 wt % in the formulation. In another
embodiment, the Sceletium extract is present from about 1 wt % to
about 25 wt % and the at least one activity enhancer is present
from about 5 wt % to about 85 wt % in the formulation. In yet
another embodiment, the Sceletium extract is present from about 2.5
wt % to about 20 wt % and the at least one activity enhancer is
present from about 1 wt % to about 50 wt % in the formulation. In a
further embodiment, the Sceletium extract is present from about 3
wt % to about 15 wt % and the at least one activity enhancer is
present from about 1 wt % to about 75 wt % in the formulation.
[0042] The formulation can include various ratios of the activity
enhancer to the Sceletium extract. In one example, the weight ratio
of amount of the activity enhancer to the amount of the Sceletium
extract can be from about 1:1 to about 20:1. In another example,
the weight ratio of the amount of the activity enhancer to the
amount of the Sceletium extract can be from about 2:1 to about
15:1. In a further embodiment, the weight ratio of the amount of
the activity enhancer to the amount of the Sceletium extract can be
from about 1:1 to about 1:20. In yet another example, the weight
ratio of the amount of the activity enhancer to the amount of the
Sceletium extract can be from about 0.25:1 to about 20:1. In yet
another example, the weight ratio of the amount of the activity
enhancer to the amount of the Sceletium extract can be from about
2.5:1 to about 14:1. In yet still another example, the weight ratio
of the amount of the activity enhancer to the amount of the
Sceletium extract can be from about 0.25:10 to about 14:1.
[0043] In some embodiments, the formulation can include a
pharmaceutically acceptable carrier. While the type of
pharmaceutically acceptable carrier/vehicle employed in generating
the disclosed formulations can vary depending upon the mode of
administration of the composition, generally pharmaceutically
acceptable carriers are physiologically inert and non-toxic. In
some embodiments, the pharmaceutically acceptable carrier can be a
pharmaceutical grade compound. Exemplary suitable carriers include
water, magnesium carbonate, talc, sugar, lactose, pectin, dextrin,
starch (from corn, wheat, rice, potato, or other plants), gelatin,
tragacanth, a low melting wax, cocoa butter, sucrose, mannitol,
sorbitol, cellulose (such as methyl cellulose,
hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose),
and gums (including arabic and tragacanth), as well as proteins
such as gelatin and collagen. In one embodiment, the carrier can
comprise cellulose, gelatin, water, or a mixture thereof.
[0044] In some embodiments, the formulations can comprise
pharmaceutically acceptable excipients. Exemplary pharmaceutically
acceptable excipients can be selected from the group consisting of
coatings, isotonic and absorption delaying agents, binders,
adhesives, lubricants, disintergrants, coloring agents, flavoring
agents, sweetening agents, absorbents, detergents, and emulsifying
agents. When the formulation includes an emulsifying agent, the
emulsifiers can be added to improve the stability of the final
product. Exemplary emulsifiers include, but are not limited to,
lecithin (e.g., from egg or soy), or mono- and di-glycerides. Other
emulsifiers are readily apparent to the skilled artisan and
selection of suitable emulsifier(s) will depend, in part, upon the
formulation and final product.
[0045] Various formulation embodiments can further include
flavorings, coloring agents, spices, nuts, preservatives,
antioxidants, vitamins, minerals, proteins, fats, and/or
carbohydrates. The amount of other ingredients can vary based on
the particular design, intended dosage, and method of
administration. The total amount of other ingredients can also
depend, in part, upon the condition and weight of the subject.
[0046] Flavors, coloring agents, spices, nuts and the like can be
incorporated into the product. Flavorings can be in the form of
flavored extracts, volatile oils, chocolate flavorings (e.g.,
non-caffeinated cocoa or chocolate, chocolate substitutes such as
carob), peanut butter flavoring, cookie crumbs, crisp rice, vanilla
or any commercially available flavoring. Flavorings can be
protected with mixed tocopherols. Examples of useful flavorings
include but are not limited to pure anise extract, imitation banana
extract, imitation cherry extract, chocolate extract, pure lemon
extract, pure orange extract, pure peppermint extract, imitation
pineapple extract, imitation rum extract, imitation strawberry
extract, or pure vanilla extract; or volatile oils, such as balm
oil, bay oil, bergamot oil, cedar wood oil, cherry oil, walnut oil,
cinnamon oil, clove oil, or peppermint oil; peanut butter,
chocolate flavoring, vanilla cookie crumb, butterscotch or toffee.
In one embodiment, the formulation can contain berry or other fruit
flavors. The food compositions may further be coated, for example
with a yogurt coating.
[0047] Preservatives can be added to the formulation to extend the
shelf life of the product. Exemplary preservatives include
potassium sorbate, sodium sorbate, potassium benzoate, sodium
benzoate, or calcium disodium EDTA.
[0048] The formulation can also include natural or artificial
sweeteners. In one embodiment, the potential sweeteners can include
glucose, sucrose, fructose, saccharides, cyclamates, aspartamine,
sucralose, aspartame, acesulfame K, sorbitol, or a combination
thereof.
[0049] The formulation can further include pharmaceutically
acceptable forms of vitamins, minerals, and other nutrients. The
nutrients chosen for inclusion in the formulation can vary
depending on the particular design, intended dosage, method of
administration, and condition of the subject. Individuals skilled
in the art are aware of vitamins, minerals, and other nutrients
that can be incorporated into formulations and how to incorporate
these.
[0050] The components in the formulation can be included as salts.
In particular, pharmaceutically acceptable salts of the components
are contemplated. A "pharmaceutically acceptable salt" is a
combination of a compound and either an acid or a base that forms a
salt (such as, for example, the magnesium salt, denoted herein as
"Mg" or "Mag") with the compound. Pharmaceutically acceptable salts
can be tolerated by a subject under therapeutic conditions. In
general, a pharmaceutically acceptable salt of a compound will have
a therapeutic index (the ratio of the lowest toxic dose to the
lowest therapeutically effective dose) of 1 or greater. Those
skilled in the art recognize that the lowest therapeutically
effective dose will vary from subject to subject and from
indication to indication, and will thus adjust the formulation
accordingly.
[0051] The formulation can be provided in any convenient form. When
the formulation is formulated in an oral dosage form, the
formulation can comprise a capsule, tablet, powder, suspension,
gel, liquid, beverage, syrup, or a food. In one embodiment, the
formulation may be formulated as powder that can be mixed with
consumable liquids, such as milk, juice, sodas, water, or
consumable gels or syrups for mixing into other nutritional liquids
or foods. The formulation can also be formulated to include
pre-measured supplemental foods, such as single serving beverages
or bars. In one embodiment, the formulation can be formulated into
a nutritional beverage. In yet other embodiments, the formulation
can be made in a variety of forms, such as pudding, confections
(i.e., candy), ice cream, frozen confections and novelties, or
non-baked, extruded food products such as bars. In one embodiment,
the manufacture of a food bar can comprise adding the dry
ingredients with the liquid ingredients in a mixer and mixing until
the dough phase is reached; the dough is then put into an extruder
and extruded; the extruded dough is then cut into appropriate
lengths, and the product is left to cool. The formulation can also
be provided as a cream or lotion for topical application. One
trained in the art can readily formulate the present composition
into any of these convenient forms for oral or topical
administration.
[0052] When formulated in an oral dosage form, the formulation can
comprise from about 0.01 mg to about 30,000 mg, from about 0.01 mg
to about 10,000 mg, from about 0.01 mg to about 5,000 mg, or from
about 0.01 mg to about 100 mg of the Sceletium extract.
[0053] Also, presented herein is a Sceletium extract dosage form
for administration to a subject to inhibit phosphodiesterase type
IV (PDE4) activity. The extract dosage includes an amount of a
Sceletium extract and an amount of at least one activity enhancer.
The dosage form when administered to a subject is more effective at
inhibiting PDE4 than either the amount of Sceletium extract or the
amount of the activity enhancer alone. While the dosage form can
vary, the dosage form can be made appropriate to the route of
administration, the disease or condition being treated, and the
subject.
[0054] The Sceletium extract in the dosage form, can be as
described above, and comprise any parts of or material derived from
the raw materials of a Sceletium species. In one exemplary
embodiment, the Sceletium extract in the dosage form is from at
least one of S. tortuosum, S. strictum, S. subvelutinum, S.
joubertii, and S. namaquense or a combination thereof. The
Sceletium extract in the dosage form can be present in a
therapeutically effective amount without the activity enhancer, or
the Sceletium extract can be present in an amount that is not
therapeutically effective without the activity enhancer. In other
words, the Sceletium extract can be in an amount that is
insufficient to provide a therapeutic effect, but with the presence
of the activity enhancer, the amount may become sufficient to have
a therapeutic effect due to the increased activity provided by the
activity enhancer.
[0055] The amount of the Sceletium extract in the dosage can vary
from about 0.01 mg to about 30,000 mg, from about 0.01 mg to about
10,000 mg, from about 0.01 mg to about 5,000 mg, or from about 0.01
mg to about 100 mg. In another embodiment, the amount of the
Sceletium extract in the dosage can vary from about 0.1 mg to about
100 mg, from about 0.1 mg to about 1,000 mg, from about 0.1 mg to
about 5,000 mg, from about 0.1 mg to about 10,000 mg, from about
0.25 mg to about 100 mg, from about 0.25 mg to about 1,000 mg, from
about 0.25 mg to about 5,000 mg, from about 0.25 mg to about 10,000
mg, from about 0.5 mg to about 100 mg, from about 0.5 mg to about
1,000 mg, from about 0.5 mg to about 5,000 mg, or from about 0.5 mg
to about 10,000 mg. In a further embodiment, the amount of the
Sceletium extract in the dosage form can vary from about 1 mg to
about 100 mg, from about 1 mg to about 1,000 mg, from about 1 mg to
about 5,000 mg, from about 1 mg to about 10,000 mg, or from about 1
mg to about 30,000 mg.
[0056] In one embodiment, the Sceletium extract can have a
standardized alkaloid content, such as total alkaloids. In one
example, the content can be from about 1 mg to about 300 mg. In
another example, the amount can be from about 5 mg to about 200 mg.
In a further example, the amount can be from about 10 mg to 100 mg.
In yet another example, the amount can be from about 20 mg to about
30 mg. In another example, the alkaloid content can be standardized
at about 25 mg.
[0057] The activity enhancer can be in the form of an extract,
compound, mineral, pharmaceutically acceptable salt, or any other
suitable form capable of being placed in the dosage form, and can
be any compound or agent suitable for use as an activity enhancer
for a Sceletium extract, including the exemplary compounds and
agents recited herein. In one exemplary embodiment, the activity
enhancer can be a member selected from the group consisting of:
L-theanine, thiamine, zinc gluconate, magnesium citrate, magnesium
stearate, cellulose, or a mixture thereof. The amount of the
activity enhancer in the dosage form can vary from about 0.01 mg to
about 60,000 mg, from about 0.01 mg to about 40,000 mg, from about
0.01 mg to about 20,000 mg, from about 0.01 mg to about 10,000,
from about 0.01 mg to about 5,000 mg, from about 0.01 mg to about
1,000 mg, or from about 0.01 mg to about 125 mg. In another
embodiment, the amount of the activity enhancer in the dosage form
can vary from about 0.1 mg to about 150 mg, from about 0.1 mg to
about 1,000 mg, from about 0.1 mg to about 5,000 mg, from about 0.1
mg to about 10,000 mg, from about 0.25 mg to about 150 mg, from
about 0.25 mg to about 1,000 mg, from about 0.25 mg to about 5,000
mg, from about 0.25 mg to about 10,000 mg, from about 0.5 mg to
about 150 mg, from about 0.5 mg to about 1,000 mg, from about 0.5
mg to about 5,000 mg, or from about 0.5 mg to about 10,000 mg. In a
further embodiment, the amount of the activity enhancer extract in
the dosage can vary from about 1 mg to about 125 mg, from about 1
mg to about 500 mg, from about 1 mg to about 1,000 mg, from about 1
mg to about 5,000 mg, from about 1 mg to about 10,000 mg, or from
about 1 mg to about 60,000 mg. These amounts can be for a single
activity enhancer, or for a combination thereof.
[0058] In one exemplary embodiment, the Sceletium extract is
present from about 1 mg to about 100 mg and the at least one
activity enhancer is present from about 1 mg to about 125 mg. In
another embodiment, the Sceletium extract is present from about
0.01 mg to about 10,000 mg and the at least one activity enhancer
is present from about 0.01 mg to about 10,000 mg. In yet another
embodiment, the Sceletium extract is present from about 1 mg to
about 30,000 mg and the at least one activity enhancer is present
from about 1 mg to about 60,000 mg. In a further embodiment, the
Sceletium extract is present from about 0.25 mg to about 1,000 mg
and the at least one activity enhancer is present from about 0.25
mg to about 5,000 mg.
[0059] The dosage form can be administered using a dosage unit
according to a pre-determined regimen. The term "dosage unit" is
understood to mean a unitary, i.e. a single dose which is capable
of being administered to a patient. The dosage unit can be readily
handled and packed, while remaining as a physically and chemically
stable unit dose comprising either the active ingredient or a
mixture of active ingredient(s) with a solid or liquid
pharmaceutical vehicle. The pre-determined regimen can be
administered once per day or multiple times per day. When the
regimen is administered multiple times per day, the regimen can be
administered once per day, twice per day, three times per day, four
times per day, or five times per day. The regimen could also be
administered on an every other day, every three days, every five
days, every week, every other week or on a monthly basis. The exact
regimen can vary based on the amounts of Sceletium extract and
activity enhancer in the dosage form, the disease be treated, and
the subject's individual characteristics and needs. In some
embodiments, the dosing regimen can be on an "as needed" basis. For
example, at the time a subject perceives the onset of signs or
symptoms of a condition (i.e. an anxiety episode), the subject can
administer a suitable dose. In alternative embodiments, the dose
can be taken according to a specific pre-set regimen as mentioned
herein.
[0060] The dosage form can be in any of a wide variety of forms.
The dosage form can be an oral, transdermal, transmucosal,
inhalation, rectal, ophthalmic (including intra-vitreal or
intracameral), nasal, topical (including buccal and sublingual),
vaginal, or parenteral (including subcutaneous, intramuscular,
intravenous, intra-dermal, and intra-tracheal) dosage form. When
the dosage form is an oral dosage, the formulation can be in the
form of discrete units such as capsules, sachets, tablets, soft
gels or lozenges, each containing a predetermined amount of the
active ingredient; in the form of a powder or granules; in the form
of a solution or a suspension in an aqueous liquid or non-aqueous
liquid, such as ethanol or glycerol; or in the form of an
oil-in-water emulsion or a water-in-oil emulsion. The active
ingredient may also be administered in the form of a bolus,
electuary or paste. When the dosage form is in the form of a depot,
the formulation may be administered by implantation (e.g.
subcutaneously, intra-abdominally, or intramuscularly) or by
intramuscular injection. Thus, for example, the active ingredient
may be formulated with suitable polymeric or hydrophobic materials
(for example, as an emulsion in a pharmaceutically acceptable oil),
or an ion exchange resin. In addition, the dosage form can be in
the form of a sustained release formulation. In one exemplary
embodiment, polymers or other ingredients can be added to create
the sustained release dosage form.
[0061] Also presented herein are methods of inhibiting
phosphodiesterase type IV (PDE4) activity in a subject. Such
methods generally comprise administering an amount of Sceletium
extract and at least one activity enhancer to a subject. As
discussed above, the Sceletium extract is any part of or a material
derived from the raw materials of a Sceletium species. Also as
discussed above, the activity enhancer is any agent that increases
PDE4 inhibition when combined with Sceletium extract. In one
exemplary embodiment, the activity enhancer can be a member
selected from the group consisting of: L-theanine, thiamine, zinc
gluconate, magnesium citrate, magnesium stearate, cellulose, or
mixtures thereof. The activity enhancer is any agent that increases
PDE4 inhibition when combined with Sceletium extract. In some
embodiments of the method, the inhibiting effect is greater than an
inhibitory effect provided by either the amount of the Sceletium
extract or the amount of activity enhancer alone. In one
embodiment, the Sceletium extract is present in a therapeutically
effective amount, and in another embodiment it is present in an
amount that becomes therapeutically effective in the presence of
the activity enhancer.
[0062] In some embodiments, the formulations and dosage forms can
be used to provide treatment of a subject that displays or
anticipates signs or symptoms of a disease or condition selected
from the group consisting of: anxiety related disorders, depression
related disorders, allergic disorders, autoimmune disorders,
diabetes associated disorders, inflammatory conditions,
neurological disorders, or cardiovascular diseases. In one
exemplary embodiment the disease or condition is an anxiety related
disorder. In another exemplary embodiment, the disease or condition
is a depression related disorder.
[0063] Allergic disorders refer to those conditions and/or diseases
that are related to PDE4 activity. Allergic disorders can be an
exaggerated or pathological reaction (as by sneezing, respiratory
distress, itching, or skin rashes) to substances, situations, or
physical states that are without comparable effect on the average
individual.
[0064] Autoimmune diseases result from a dysfunction of the immune
system in which the body produces autoantibodies that attack its
own organs, tissues and cells. Autoimmune diseases can be process
mediated via protein phosphorylation through PDE4.
[0065] Diabetes associated disorders refers to insulin related
disorders. Insulin related disorders are diseases or conditions
where the response to insulin is either causative of the disease or
has been implicated in the progression or suppression of the
disease or condition. Representative examples of insulin related
disorders include, without limitation diabetes (both type 1 and
type 2), diabetic complications, insulin sensitivity, polycystic
ovary disease, hyperglycemia, dyslipidemia, insulin resistance,
metabolic syndrome, obesity, body weight gain, inflammatory
diseases, diseases of the digestive organs, stenocardia, myocardial
infarction, sequelae of stenocardia or myocardial infarction,
senile dementia, and cerebrovascular dementia.
[0066] Inflammatory conditions are local responses to cellular
injury that are marked by capillary dilatation, leukocytic
infiltration, redness, heat, pain, swelling, and/or loss of
function. Inflammatory conditions serve as a mechanism initiating
the elimination of noxious agents and of damaged tissue. Systemic
inflammatory responses can produce "flu-like" symptoms, such as,
for instance, fever, chills, fatigue/loss of energy, headaches,
loss of appetite, and muscle stiffness. Examples, without
limitation, of inflammatory conditions include diseases of the
digestive organs (such as ulcerative colitis, Crohn's disease,
pancreatitis, gastritis, benign tumor of the digestive organs,
digestive polyps, hereditary polyposis syndrome, colon cancer,
rectal cancer, stomach cancer and ulcerous diseases of the
digestive organs), stenocardia, myocardial infarction, sequelae of
stenocardia or myocardial infarction, senile dementia,
cerebrovascular dementia, immunological diseases and cancer in
general.
[0067] Neurological disorders refer to any disturbance in the
structure or function of the central nervous system resulting from
developmental abnormality, disease, injury or toxin.
Representative, non-limiting examples of neurological disorders
include Alzheimer's disease, type 3 diabetes, Parkinson's disease,
multiple sclerosis, amyotrophic lateral sclerosis (ALS or Lou
Gehrig's Disease), Huntington's disease, neurocognitive
dysfunction, senile dementia, and mood disorder diseases.
[0068] Cardiovascular diseases refer to those pathologies or
conditions that impair the function of, or destroy cardiac tissue
or blood vessels.
[0069] The methods disclosed can be used on any subject that would
benefit from PDE4 inhibition. In one exemplary embodiment, the
subject is a mammal. In another embodiment mammals include humans.
In other exemplary embodiments, mammals include non-human mammals.
Non-human mammals can include domesticated animals, such as cats
and dogs, as well as farm animals such as horses and cows, mice,
and rats.
[0070] In one embodiment, the present formulations and dosage forms
can be administered to a subject that is suffering from a PDE4
related condition or disease, or the method can be administered
prophylactically in order to prevent the occurrence or progression
of a PDE4 related condition or disease. The formulation or dosage
used can be administered in the form of an oral, transdermal,
transmucosal, rectal, ophthalmic (including intravitreal or
intracameral), nasal, nasal by inhalation, topical (including
buccal and sublingual), vaginal, parenteral (including
subcutaneous, intramuscular, intravenous, intradermal, and
intratracheal), by implantation, or intramuscularly. In one
exemplary embodiment the method administers the formulation orally.
The method can include administering the Sceletium extract and the
at least one activity enhancer concurrently. When administered
concurrently, the Sceletium extract and at least one activity
enhancer can be administered from a single formulation. In another
embodiment, the Sceletium extract and at least one activity
enhancer are administered separately. In yet another embodiment,
the Sceletium extract and the at least one activity enhancer are
administered sequentially.
[0071] In one embodiment a method of treating a PDE4 related
condition in a subject can comprise administering an amount of a
Sceletium extract and an activity enhancer. In one embodiment, the
amount of Sceletium extract per dose can be about 25 mg and the
daily amount of the activity enhancer per dose can be about 515 mg.
In another embodiment, the amount of the Sceletium extract per dose
can be about 30 mg and the amount of the activity enhancer per dose
can be about 60 mg. In yet another embodiment, the amount of the
Sceletium extract per dose can be about 100 mg and the amount of
the activity enhancer per dose can be about 125 mg. In a further
embodiment, the amount of the Sceletium extract per dose can be
about 100 mg and the amount of the activity enhancer per dose can
be about 4,000 mg. While exemplary dosage amounts are presented
above, the exact dosage amount will vary based on the disease or
condition being treated and the individual needs and
characteristics of the subject.
[0072] In an additional invention embodiment, there is presented a
method of increasing the phosphodiesterase type IV (PDE4)
inhibition activity of an amount of a Sceletium extract. In one
aspect, such a method comprises adding or combining an amount of at
least one activity enhancer with the administration of the
Sceletium extract. The Sceletium extract and the activity enhancer
can be included in the method as described above. The combination
of the Sceletium extract and the activity enhancer inhibits PDE4
activity to a greater degree than the amount of the Sceletium
extract alone. In some embodiments, the increase in inhibition
attained can be greater than the additive effect of each ingredient
alone (i.e. synergistic). In one embodiment, the Sceletium extract
and activity enhancer can be combined in a single formulation, or
can be in separate formulations that are combined upon
administration to the subject. For example, the Sceletium and
activity enhancer can be administered to a subject in such a manner
that they combine or effectively combine in vivo. In one
embodiment, they Sceletium extract and the activity enhancer can be
administered concurrently. In another embodiment they can be
administered sequentially or otherwise at separate times as long as
they are still able to provide the enhanced PDE4 inhibitory
effect.
[0073] Further presented is a phosphodiesterase type IV (PDE4)
inhibiting system. The inhibiting system comprises an amount of a
Sceletium extract and an amount of at least one activity enhancer.
Presented more fully above, are exemplary embodiments of the
Sceletium extract and the activity enhancer use in the system, as
well as, the PDE4 inhibiting activity of the system, for example
the dosages and formulations set forth. The Sceletium extract and
the activity enhancer can be separately assembled in the system. In
some embodiments the Sceletium extract and activity enhancer are in
separate formulations. When the Sceletium extract and activity
enhancer are in separate formulations they can be packaged together
or packaged individually. In other embodiments, the Sceletium
extract and activity enhancer are in a single formulation.
Regardless of the embodiment, the formulation can be in a form that
masks the taste of the Sceletium extract and/or the activity
enhancer (e.g., capsule or pill form) rather than incorporating
them into a food or beverage (e.g., powder or bar). Separate
formulations or dosages of Sceletium extract and activity enhancer
can each include numerous other ingredients, such as carriers,
excipients, etc.
[0074] The system can optionally include additional components. In
one embodiment, the system can be associated a container(s). In
some embodiments, the system can include a notice in the form
prescribed by a government agency regulating the manufacture, use
or sale of pharmaceutical products, which notice reflects approval
by the agency of manufacture, use of sale for human administration.
Furthermore, the system can be labeled with information (i.e.
instructions) regarding mode of administration, sequence of
administration (e.g., separately, sequentially or concurrently), or
the like. Alternatively, such information can be included in a
sheet or booklet separate from the product label. The system can
also include means for reminding the patient to take the Sceletium
extract and activity enhancer. The system can be a single unit
dosage of the Sceletium extract and activity enhancer or it can be
a plurality of unit dosages.
[0075] Further presented is a method for modulating protein kinase
activity in a subject. As previously discussed PDE4 inhibitors can
prolong or enhance the effects of a variety of physiological
processes mediated by cAMP. The process can occur in a wide range
of tissues through inhibition of cyclic nucleotide degradation. The
modulation of the downstream signaling pathways relating to cAMP
directly affects protein kinase activity. Certain protein kinases
are only activated when cAMP is present. Therefore, the
formulations previously discussed can be used in a method for
modulating protein kinase activity.
[0076] The method includes administering to a subject a formulation
having an amount of Sceletium extract in combination with an amount
of at least one activity enhancer. The Sceletium extract and
activity enhancer are included in the formulation as discussed
above. In one embodiment when the formulation is administered to a
subject, the formulation is more effective at modulating protein
kinase activity then either the amount of Sceletium extract or the
amount of activity enhancer alone. In one embodiment, the protein
kinase activity that is modulated is a protein kinase selected from
the group consisting of ABL, AKT, AURORA, CDK, DBF2/20, EGFR,
EPH/ELK/ECK, ERK/MAPKFGFR, GSK3, IKKB, INSR, JAK DOM 1/2,
MARK/PRKAA, MEK/STE7, MEKK/STE11, MLK, mTOR, PAK/STE20, PDGFR,
PI3K, PKC, POLO, SRC, TEC/ATK, and ZAP/SYK. In a second embodiment,
the protein kinase activity that is modulated is a protein kinase
selected from the group consisting of CLK1, Met, Syk, Aurora, PRAK,
Flt4, TrkC, CK2.alpha.2, MSSk1, Fms, and GSK3. Regulation of
protein kinase activity is useful as a treatment for disease states
or conditions because of the relationship between protein kinase
activity and disease states and conditions. While not being bound
by theory, it is believed that the relationship is either causative
of the disease or intimately related to the expression and
progression of disease-associated symptomology and pathology.
[0077] Further presented is a method of preparing a PDE4 inhibiting
formulation. The method includes combining the Sceletium extract
with at least one activity enhancer in a manner suitable for
administration to a subject. The Sceletium extract with at least
one activity enhancer includes those extracts and enhancers as
previously discussed above. The method includes method of
formulating compositions that are well known in the art. All
methods include the step of bringing the active ingredient into
association with the vehicle that constitutes one or more auxiliary
constituents. In one embodiment, the method can include acquiring a
source of a Sceletium extract and formulating the Sceletium extract
with the activity enhancer(s). The formulation can be further
formulated with a pharmaceutically acceptable carrier and/or other
excipients, preservatives or additives. In one embodiment, the
method further includes the step of extracting the Sceletium
extract from a Sceletium sp. or spp. prior to combining the
Sceletium extract with the activity enhancer(s). The Sceletium sp.
or spp. can be extracted using any known extraction methods. When
the extraction is a liquid extraction the extraction can occur
using any suitable solvent including, organic solvents, inorganic
solvents, ethanol, water, steam, superheated water, methanol,
ethanol, hexane, chloroform liquid, liquid CO.sub.2, liquid
N.sub.2, propane, supercritical CO.sub.2 or any combination
thereof. In a further embodiment, the material that the Sceletium
extract is derived from can be milled prior to being extracted.
[0078] Embodiments of the present disclosure will be described with
reference to the following Examples which are provided for
illustrative purposes only and should not be used to limit the
scope of or construe the invention.
Examples
Example 1
Formulation of S. tortuosum
[0079] Dry aerial parts of S. tortuosum were cultivated and
prepared commercially by HG&H Pharmaceutical (Pty) Ltd, South
Africa. The air dried S. tortuosum was milled using a conventional
industrial milling machine. The milling occurred in a hammer mill
with a mesh size adjusted to achieve a particle size >85 microns
and <3 mm. The milled powder was added to an aqueous ethanoic
solution comprising 70% ethanol. The ratio of raw milled plant
material to extraction liquid was 1:6 w/w. The solution and milled
powder were stirred with an electric stirrer. The temperature of
the solution was maintained between 25.degree. C.-50.degree. C. and
was continually and slowly stirred for 24 hours. Following the
stirring, the solution was filtered through a commercial filter
with an appropriate mesh size to yield the desired filtrate. The
filtrate was spray-dried onto lactose monohydrate.
Example 2
Phosophodiesterase Inhibition
[0080] The ethanoic extract of S. tortuosum was tested for the
capacity to inhibit four phosphodiesterases in a concentration
dependent manner. The sample was tested at 10 concentrations with
2-fold serial dilutions starting at 125 .mu.g/mL. Each assay was
accompanied by a dose-response series of the control compound
3-isobutyl-1-methylxanthine (IBMX); positive controls were also
tested at 10-concentrations with 3-fold serial dilutions starting
at 100 .mu.M.
[0081] The incubation mixture contained 10 mM Tris, pH 7.5, 5 mM
MgCl2, 0.01% Brij 35, 1 mM dithiothreitol, and 1% dimethylsulfoxide
(DMSO). For PDE1A, 0.2 mM CaCl.sub.2 and 0.36 M calcium/calmodulin
were included in the reaction mixture. Test material was added in
DMSO, followed by addition of cAMP to a final concentration of 1
.mu.M. After one hour at ambient temperature, the reaction was
stopped by the addition of a proprietary Stop/detection mixture.
Fluorescence polarization was measured after another 90 minutes
incubation at room temperature. AMP was quantified for each
concentration using the Transcreener.RTM. fluorescence polarization
assay (BellBrook Labs, Madison, Wis.) with Ex=620 nm FP and Em=688
nm P and S.
[0082] The IC.sub.50 values (concentrations producing half maximal
inhibition of control specific activity) and Hill coefficients were
determined by non-linear regression analysis of the inhibition
curves using Hill equation curve fitting
(Y=D+[(A-D)/(1+C/C.sub.50).sup.nH)] using GraphPad Prism software
(GraphPad Software, La Jolla, Calif.). Curve fits were performed
from the point where the inhibitory activity at the highest
concentration of compound was less than 65%. IC.sub.50 values are
presented in Table A as .mu.g sample/mL.
TABLE-US-00001 TABLE A Median Inhibitory Concentration of S.
tortousum against PDE1A, PDE2A, PDE3A and PDE4D Median Inhibitory
Concentration IC.sub.50 Value S. tortuosom Controls Enzyme .mu.g/ML
Test Material .mu.g/mL PDE1A -- IBMX 0.140 PDE2A -- IBMX 1.78 PDE3A
124 IBMX 0.591 PDE4D 16.7 IBMX 5.63
The organic extract of S. tortuosum, exhibited a
concentration-dependent inhibition of both PDE3A and PDE4D.
Example 3
Formulations of Sceletium Enhanced by L-Theanine and Thiamine
[0083] L-theanine and thiamine were purchased from commercial
sources. Independent testing of L-theanine and thiamine for
PDE-inhibitory activity revealed that neither compound possessed
inhibitory activity against any of the four PDE isozymes.
Preparation of the alcoholic extract of S. tortuosum was performed
as described in Example 1 and combined with the L-theanine and
thiamine. The formulation contained 50 mg of the S. tortuosum
extract, 52 mg of L-theanine, and 6.25 mg of thiamine.
Example 4
Phosphodiesterase Inhibition by Formulations Containing Sceletium,
L-Theanine and Thiamine
[0084] The effects of formulations containing S. tortuosum extract,
L-theanine, and thiamine on the inhibition of PDE4 compared to the
S. tortuosum extract alone were tested. An additional objective was
to observe the effects of the multi-component formulation on PDE1A,
PDE2A, and PDE3A.
[0085] Enzyme assays and calculations were performed as previously
described in Example 2 using the formulations prepared in Example
3. Activities were based on S. tortuosum sample content of the
reaction mixture, as all other components had demonstrated no
effect on PDEs and the alkaloid content of the S. tortuosum and the
test formulation of S. tortuosum containing L-theanine and thiamine
were balanced.
TABLE-US-00002 TABLE B Median Inhibitory Concentrations of S.
tortousum, L-theanine, and thiamine against PDE1A, PDE2A, PDE3A and
PDE4D Median Inhibitory Concentration IC.sub.50 Value S. tortousum,
L- theanine, S. and Controls tortuosum L- Thi- thiamine Test Enzyme
extract theanine* amine* sample Material .mu.g/mL PDE1A -- 0 0 --
IBMX 0.795 PDE2A -- 0 0 -- IBMX 1.41 PDE3A -- 0 0 -- IBMX 0.869
PDE4D 6.94 0 0 4.43 IBMX 3.24 *L-theanine and thiamine were tested
individually at a different date for their PDE4 inhibitory effect.
During that testing L-theanine and thiamine did not exhibit any
inhibitory activity.
[0086] The extract combining the S. tortuosum, with L-theanine and
thiamine exhibited a 36% inhibition in the PDE4 activity which is
synergistic and unexpected in view of the fact that L-theanine and
thiamine do not exhibit any PDE4 inhibitory activity when
administered alone. The addition of L-theanine and thiamine to the
S. tortuosum preparation unexpectedly increased the PDE4 inhibitory
activity 1.57-fold relative to the extract alone.
Exemplary Embodiments
[0087] The following exemplary invention embodiments pertain to
further aspects of the disclosure.
[0088] In one example there is provided, a phosphodiesterase type
IV (PDE4) activity inhibiting formulation, comprising: [0089] a
Sceletium extract in combination with at least one activity
enhancer, wherein when administered to a subject, the formulation
is more effective at inhibiting PDE4 activity than either the
Sceletium extract or the activity enhancer alone.
[0090] In one example the PDE4 inhibiting effect of the formulation
on the subject is more than an additive effect achieved by
administering the Sceletium extract or the activity enhancer
alone.
[0091] In one example, the PDE4 inhibiting effect of the
formulation on the subject is from about 30% to about 80% greater
than that achieved by administering either the Sceletium extract or
the activity enhancer alone.
[0092] In one example, the Sceletium extract in the formulation is
from at least one of S. tortuosum, S. strictum, S. subvelutinum, S.
joubertii, and S. namaquense or a combination thereof.
[0093] In one example, the Sceletium extract in the formulation is
derived from S. tortuosum.
[0094] In one example the Sceletium extract in the formulation is
derived from aerial portions of a Sceletium plant.
[0095] In one example, the Sceletium extract comprises from about 1
wt % to about 50 wt % of the formulation.
[0096] In one example, the Sceletium extract comprises from about 3
wt % to about 15 wt % of the formulation.
[0097] In one example, the activity enhancer has substantially no
PDE4 inhibitory effect of its own.
[0098] In one example, the activity enhancer in the formulation is
a member selected from the group consisting of: L-theanine,
thiamine, zinc gluconate, magnesium citrate, magnesium stearate,
cellulose, or a mixture thereof.
[0099] In one example, the activity enhancer in the formulation is
L-theanine.
[0100] In one example, the activity enhancer in the formulation is
thiamine.
[0101] In one example, the formulation comprises a plurality of
activity enhancers.
[0102] In one example the formulation comprises a plurality of
activity enhancers and the activity enhancers include L-theanine
and thiamine.
[0103] In one example, the formulation comprises a plurality of
activity enhancers and the activity enhancers include L-theanine,
thiamine, magnesium citrate, and zinc.
[0104] In one example, the formulation above further comprises
magnesium stearate.
[0105] In one example, the at least one activity enhancer in the
formulation comprises from about 1 wt % to about 75 wt % of the
formulation.
[0106] In one example, the at least one activity enhancer in the
formulation is in a form of a pharmaceutically acceptable salt.
[0107] In one example, the Sceletium extract in the formulation is
present from about 3 wt % to about 15 wt % and the at least one
activity enhancer is present in the formulation from about 1 wt %
to about 75 wt %.
[0108] In one example, the formulation further comprises a
pharmaceutically acceptable carrier.
[0109] In one example, the pharmaceutically acceptable carrier in
the formulation comprises cellulose, gelatin, water or mixtures
thereof.
[0110] In one example, the formulation further comprising at least
one member selected from the group consisting of flavorings,
preservatives, vitamins, or minerals.
[0111] In one example, the formulation is an oral dosage
formulation.
[0112] In one example, the oral dosage form comprises a capsule, a
tablet, a powder, a beverage, a syrup, a suspension, or a food.
[0113] In one example, the formulation comprises from about 0.1 mg
to about 10,000 mg of the Sceletium extract.
[0114] In one example there is provided, a Sceletium extract dosage
form for administration to a subject to inhibit phosphodiesterase
type IV (PDE4) activity comprising: [0115] an amount of a Sceletium
extract and an amount of at least one activity enhancer, wherein
when administered to a subject, the dosage is more effective at
inhibiting PDE4 than either the amount of Sceletium extract or the
amount of the activity enhancer alone.
[0116] In one example, the amount of Sceletium extract in the
dosage form is a therapeutically effective amount without the
activity enhancer.
[0117] In one example, the amount of Sceletium extract in the
dosage form is not a therapeutically effective amount without the
activity enhancer.
[0118] In one example, the amount of the Sceletium extract in the
dosage form is from about 0.01 mg to about 30,000 mg.
[0119] In one example, the amount of the Sceletium extract in the
dosage form is from about 0.01 mg to about 10,000 mg.
[0120] In one example, the amount of the Sceletium extract in the
dosage form is from about 0.1 mg to about 100 mg.
[0121] In one example, the amount of the at least one activity
enhancer in the dosage form is from about 0.01 mg to about 10,000
mg.
[0122] In one example, the amount of the at least one activity
enhancer in the dosage form is from about 1 mg to about 125 mg.
[0123] In one example, the Sceletium extract is present in the
dosage form at an amount of from about 1 mg to about 100 mg and the
at least one activity enhancer is present in an amount of from
about 1 mg to about 125 mg.
[0124] In one example, the dosage form is prepared for
administration to a subject according to a predetermined
regimen.
[0125] In one example, the dosage form is administered in the
regimen is a once per day administration.
[0126] In one example, the dosage form is administered according to
a predetermined regimen that is a multiple time per day
administration.
[0127] In one example, the dosage form is administered in an oral
dosage form, a transdermal dosage form, a transmucosal dosage form,
an inhalant dosage form, or a parenteral dosage form.
[0128] In one example there is provided, a method of inhibiting
phosphodiesterase type IV (PDE4) activity in a subject comprising:
[0129] administering an amount of a Sceletium extract and at least
one activity enhancer to the subject.
[0130] In one example, the activity enhancer used in the method is
a member selected from the group consisting of: L-theanine,
thiamine, zinc gluconate, magnesium citrate, magnesium stearate,
cellulose, or a mixture thereof.
[0131] In one example, in the method the PDE4 inhibiting effect is
greater than an effect provided by either the amount of Sceletium
extract or the amount of activity enhancer alone.
[0132] In one example, in the method the PDE4 inhibition provides
treatment of signs or symptoms of a condition selected from the
group consisting of: anxiety related disorders, depression related
disorders, allergic disorders, autoimmune disorders, diabetes
associated disorders, inflammatory conditions, neurological
disorders, or cardiovascular diseases.
[0133] In one example, the method provides treatment for an anxiety
related disorder.
[0134] In one example, the method provides treatment for a
depression related disorder.
[0135] In one example, the method is administered to a subject that
is a mammal.
[0136] In one example, the mammal is a human.
[0137] In one example, the mammal is a domesticated or farm
animal.
[0138] In one example, the method of treatment is prophylactic.
[0139] In one example of the method, the Sceletium extract and at
least one activity enhancer formulation are administered orally,
rectally, ophthalmicly, nasally, nasally by inhalation, topically,
vaginally, parentally, by implantation, or intramuscularly.
[0140] In one example, the Sceletium extract and at least one
activity enhancer are administered orally.
[0141] In one example, the Sceletium extract and at least one
activity enhancer are administered concurrently.
[0142] In one example, the Sceletium extract and at least one
activity enhancer are administered from a single formulation.
[0143] In one example, the Sceletium extract and at least one
activity enhancer are administered separately.
[0144] In one example, the Sceletium extract and the at least one
activity enhancer are administered sequentially.
[0145] In one example there is provided, a method of increasing
phosphodiesterase type IV (PDE4) inhibition activity of an amount
of a Sceletium extract comprising: [0146] adding an amount of at
least one activity enhancer, wherein the combination of Sceletium
extract and the at least one activity enhancer inhibits PDE4
activity to a greater degree than the amount of Sceletium
alone.
[0147] In one example, the PDE4 inhibition occurs in a subject to
whom the Sceletium extract and the at least one activity enhancer
are administered.
[0148] In one example, the Sceletium extract and the at least one
activity enhancer is added to a formulation containing the
Sceletium extract.
[0149] In one example, the at least one activity enhancer is added
to the Sceletium extract upon administration of the activity
enhancer to a subject.
[0150] In one example, the increase in PDE4 inhibition activity is
more than an additive effect of administering the amount of
Sceletium extract and the amount of at least one activity enhancer
alone.
[0151] In one example, the increase in PDE4 inhibition activity is
from about 30% to about 80% greater than that achieved by
administering either the Sceletium extract or the activity enhancer
alone.
[0152] In one example, the Sceletium extract is from at least one
of S. tortuosum, S. strictum, S. subvelutinum, S. joubertii, and S.
namaquense, or a combination thereof.
[0153] In one example, the Sceletium extract is from S.
tortuosum.
[0154] In one example, the at least one activity enhancer is a
member selected from the group consisting of: L-theanine, thiamine,
zinc gluconate, magnesium citrate, magnesium stearate, cellulose,
or mixtures thereof.
[0155] In one example, the at least one activity enhancer is
L-theanine.
[0156] In one example, the at least one activity enhancer is
thiamine.
[0157] In one example, the amount of at least one activity enhancer
is added to the amount of Sceletium extract at a ratio of from
about 1:1 to about 20:1.
[0158] In one example, the ratio is from about 2:1 to about 15:1 In
one example, the ratio is about 14:1.
[0159] In one example of the method, the at least one enhancer is
added in an amount of 345 mg to a formulation containing 25 mg of
Sceletium extract.
[0160] In one example there is provided a phosphodiesterase type IV
(PDE4) inhibiting system, comprising:
[0161] an amount of a Sceletium extract; and
[0162] an amount of at least one activity enhancer.
[0163] In one example, the Sceletium extract and the at least one
activity enhancer are separate from one another.
[0164] In one example, the Sceletium extract and the at least one
activity enhancer are in separate formulations.
[0165] In one example, the Sceletium extract and the at least one
activity enhancer are in a single formulation.
[0166] In one example, the amount of Sceletium extract and the
amount of at least one activity enhancer are more effective at
inhibiting PDE4 together than either the amount of Sceletium
extract or the amount of at least one activity enhancer alone.
[0167] In one example, the effect of the combined amount of
Sceletium extract and the amount of at least one activity enhancer
is more than additive.
[0168] In one example, the PDE4 inhibiting effect of the combined
amount of Sceletium extract and the amount of at least one activity
enhancer is from about 30% to about 80% greater than that achieved
by administering the amount of Sceletium extract or the amount of
activity enhancer alone.
[0169] In one example, the Sceletium extract is derived from at
least one of S. tortuosum, S. strictum, S. subvelutinum, S.
joubertii, and S. namaquense or a combination thereof.
[0170] In one example, the Sceletium extract is derived from S.
tortuosum.
[0171] In one example, the amount of the amount of Sceletium
extract is from about 0.01 mg to about 30,000 mg.
[0172] In one example, the amount of Sceletium extract is from
about 0.01 mg to about 10,000 mg.
[0173] In one example, the amount of Sceletium extract is from
about 1 mg to about 100 mg.
[0174] In one example, the amount of the at least one activity
enhancer is from about 0.01 mg to about 10,000 mg.
[0175] In one example, the amount of the at least one activity
enhancer is from about 1 mg to about 125 mg.
[0176] In one example, the Sceletium extract and the at least one
activity enhancer are packaged together.
[0177] In one example, a method for modulating a diseases-related
protein kinase activity in a subject comprising: [0178]
administering to the subject a formulation having an amount of a
Sceletium extract in combination with an amount of at least one
activity enhancer, wherein when administered to a subject, the
formulation is more effective at modulating the protein kinase
activity then either the amount of Sceletium extract or the amount
of activity enhancer alone.
[0179] In one example of the method, the disease-related protein
kinase activity is selected from the group consisting of ABL, AKT,
AURORA, CDK, DBF2/20, EGFR, EPH/ELK/ECK, ERK/MAPKFGFR, GSK3, IKKB,
INSR. JAK DOM 1/2, MARK/PRKAA, MEK/STE7, MEKK/STE11, MLK, mTOR,
PAK/STE20, PDGFR, PI3K, PKC, POLO, SRC, TEC/ATK, and ZAP/SYK.
[0180] In one example of the method, the disease related protein
kinase activity is modulated in a protein kinase selected from the
group consisting of CLK1, Met, Syk, Aurora, PRAK, Flt4, TrkC,
CK2.alpha.2, MSSk1, Fms, and GSK3.
[0181] In one example of the method, the disease related protein
kinase plays a functional role in an anxiety condition in the
subject.
[0182] In one example there is provided a method of preparing a
phosphodiesterase type IV (PDE4) activity inhibiting formulation,
comprising: [0183] combining a Sceletium extract with at least one
activity enhancer in a manner suitable for administration to a
subject.
[0184] In one example, there is provided a composition for
enhancing the PDE4-inhibitory activity of Sceletium in a subject
comprising a therapeutically effective amount of at least one
member selected from the following group comprising:
[0185] a. from about 0.01 mg to about 10,000 mg of aerial parts of
Sceletium;
[0186] b. from about 0.01 mg to about 10,000 mg of an extract of
Sceletium tortuosum;
[0187] c. from about 0.01 mg to about 10,000 mg of a compound
derived from Sceletium;
and at least one member from the following group comprising:
[0188] d. from about 0.01 mg to about 10,000 mg of L-theanine;
[0189] e. from about 0.01 mg to about 10,000 mg of thiamine;
[0190] f. from about 0.01 mg to about 10,000 mg of zinc
gluconate;
[0191] g. from about 0.01 mg to about 10,000 mg of magnesium
citrate;
[0192] h. from about 0.01 mg to about 10,000 mg of magnesium
stearate;
[0193] i. from about 0.01 mg to about 10,000 mg of cellulose.
[0194] In one example, there is provided a method for enhancing the
PDE4-inhibitory activity of Sceletium administered to a subject
comprising administering a therapeutically effective amount of at
least one member selected from the following group comprising:
[0195] a. from about 0.01 mg to about 10,000 mg of aerial parts of
Sceletium;
[0196] b. from about 0.01 mg to about 10,000 mg of an extract of
Sceletium tortuosum;
[0197] c. from about 0.01 mg to about 10,000 mg of a compound
derived from Sceletium;
and at least one member from the following group comprising:
[0198] d. from about 0.01 mg to about 10,000 mg of L-theanine;
[0199] e. from about 0.01 mg to about 10,000 mg of thiamine;
[0200] f. from about 0.01 mg to about 10,000 mg of zinc
gluconate;
[0201] g. from about 0.01 mg to about 10,000 mg of magnesium
citrate;
[0202] h. from about 0.01 mg to about 10,000 mg of magnesium
stearate;
[0203] i. from about 0.01 mg to about 10,000 mg of cellulose.
[0204] Thus, there have been disclosed novel compositions of
Sceletium and/or Sceletium extract, such as S. tortuosum and
methods of synergistically inhibiting PDE4. Methods for the
production of these formulations and uses have been described. It
will be readily apparent to those skilled in the art, however that
various changes and modifications of an obvious nature may be made
without departing from the spirit of the disclosed invention
embodiments, and all such changes and modifications are considered
to fall within the scope of the invention as recited herein,
including in the appended claims. Examples of such changes and
modifications could include, but not be limited to, the incipient
ingredients added to affect the capsule, tablet, powder, lotion,
food or bar manufacturing process as well as vitamins, flavorings
and carriers. Other examples of such changes or modifications could
include the use of herbs or other botanical products containing the
combinations of the preferred embodiments disclosed above.
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